Time-dependent changes in the activation of RhoA/ROCK and ERM/p-ERM in the increased expression of intestinal P-glycoprotein by repeated oral treatment with etoposide

Previously, we reported that repeated oral treatment with etoposide (ETP) increased ileal membrane localization of P-glycoprotein (P-gp) and that this was possibly mediated by increased expression of the ezrin/radixin/moesin (ERM)/phosphorylated ERM (p-ERM) via activation of RhoA/ROCK. These changes caused decreases in the analgesia of oral morphine (substrate drug for P-gp). However, there are no reports indicating the temporal changes in the above-mentioned factors after initiation and cessation of repeated treatment with the substrate drugs for P-gp including ETP. We examined the relationships between time-dependent changes in protein expressions of ileal P-gp and those of RhoA, ROCK, ERM, and p-ERM, and in oral morphine analgesia after initiation or cessation of repeated oral treatment with ETP. Ileal membrane localization of RhoA was increased 3 days after initiating ETP treatment; on 5 or 7 days, that of ROCK, ERM, and p-ERM was increased along with increments in P-gp expression, leading to decreases in oral morphine analgesia. All these changes returned toward normal levels 3 days after cessation. These data suggest that regulating the active state of the above-mentioned proteins during cancer chemotherapy or creating a timeframe of discontinuation a few days after cessation may enable effective palliative care using oral opioids. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:16701682, 2013